Loss of heterozygosity of essential genes represents a widespread class of potential cancer vulnerabilities

Caitlin A Nichols,John P Busanovich,William J Gibson,Naomi Curimjee,Ashton C Berger,Andrew D Cherniack,Rameen Beroukhim,Galen F Gao,Sirano Dhe-Paganon,Brenton R Paolella,Meredith S Brown,Jack A Kosmicki,Hope Wei,Laura M Urbanski

doi:10.1038/s41467-020-16399-y

Abstract

Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. Hundreds to thousands of non-driver genes undergo loss of heterozygosity (LOH) events per tumor, generating discrete differences between tumor and normal cells. Here we interrogate LOH of polymorphisms in essential genes as a novel class of therapeutic targets. We hypothesized that monoallelic inactivation of the allele retained in tumors can selectively kill cancer cells but not somatic cells, which retain both alleles. We identified 5664 variants in 1278 essential genes that undergo LOH in cancer and evaluated the potential for each to be targeted using allele-specific gene-editing, RNAi, or small-molecule approaches. We further show that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8) reduces growth of cells harboring that allele, while cells harboring the non-targeted allele remain intact. We conclude that LOH of essential genes represents a rich class of non-driver cancer vulnerabilities.

Highlights

Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer
Loss of heterozygosity (LOH) occurs when a cancer cell that is originally heterozygous at a locus loses one of its two alleles at that locus, either by simple deletion of one allele, or by deletion of one allele accompanied by duplication of the remaining allele
We integrated genome-wide gene essentiality data from loss-of-function genetic screens and CCLE cell lines to conservatively estimate 1481 genes that are essential across lineages (Supplementary Data 1; Methods). This list is enriched for genes involved in essential cellular processes including rRNA processing, mRNA splicing, and translation

Summary

Introduction

Alterations in non-driver genes represent an emerging class of potential therapeutic targets in cancer. When a cancer cell undergoes LOH of an essential gene, further loss or inhibition of the allele retained in the tumor should not be tolerated, whereas normal cells will be able to survive relying solely on the remaining allele[3] (Fig. 1a). We term this target class GEMINI vulnerabilities, after the twins from Greek mythology Castor and Pollux, one of which was mortal and the other immortal. These results rigorously validate the GEMINI class of vulnerabilities and define its potential scope

Methods

Results

Conclusion